The effect of nitric oxide on cell respiration: A key to understanding itsrole in cell survival or death

The mitochondrion is a key organelle in the control of cell death. Nitric o xide (NO) inhibits complex IV in the respiratory chain and is reported to p ossess both proapoptotic and antiapoptotic actions. We investigated the eff ects of continuous inhibition of respiration by NO on mitochondrial energy status and cell viability. Serum-deprived human T cell leukemia (Jurkat) ce lls were exposed to NO at a concentration that caused continuous and comple te (similar to 85%) inhibition of respiration. Serum deprivation caused pro gressive loss of mitochondrial membrane potential (Delta psi (m)) and apopt otic cell death. In the presence of NO, Delta psi (m), was maintained compa red to controls, and cells were protected from apoptosis. Similar results w ere obtained by using stauroporin as the apoptotic stimulus. As exposure of serum-deprived cells to NO progressed (>5 h), however, Delta psi (m), fell , correlating with the appearance of early apoptotic features and a decreas e in cel viability. Glucose deprivation or iodoacetate treatment of cells i n the presence of NO resulted in a collapse of Delta psi (m), demonstrating involvement of glycolytic ATP in its maintenance. Under these conditions c ell viability also was decreased. Treatment with oligomycin and/or bongkrek ic acid indicated that the maintenance of Delta psi (m), during exposure to NO is caused by reversal of the ATP synthase and other electrogenic pumps. Thus, blockade of complex IV by NO initiates a protective action in the mi tochondrion to maintain Delta psi (m); this results in prevention of apopto sis. It is likely that during cellular stress involving increased generatio n of NO this compound will trigger a similar sequence of events, depending an its concentration and duration of release.